1. Field of the Invention
This invention relates to novel xcex1-aryl-N-alkylnitrones and their use as therapeutic agents and analytical reagents. More particularly, this invention concerns novel xcex1-aryl-N-alkylnitrones and their use as therapeutics for treating and/or preventing neurological, autoimmune and inflammatory conditions in mammals and as analytical reagents for detecting free radicals.
2. State of the Art
Alzheimer""s disease is a neurodegenerative condition in which nerve cells in the brain are systematically destroyed resulting in progressive memory loss, mental confusion and ultimately death. The National Institute on Aging (NIA) has recently estimated that about 4 million people in the United States are currently afflicted with Alzheimer""s disease. At present, there is no treatment that effectively prevents the disease or reverses its symptoms.
In recent years, significant progress has been made in understanding the pathogenesis of Alzheimer""s disease. For example, it is now known that patients with Alzheimer""s disease develop amyloid plaque deposits around and between the nerve cells of their brain. These plaque deposits are made up of fibrillar aggregates of a small peptide called amyloid xcex2-peptide or Axcex2. The plaque deposits initially form in the hippocampus and cortical regions of the brain (areas associated with memory and cognition) and then spread to other areas as the disease progresses. The deposition of fibrils and plaques is also followed by inflammation of the surrounding support cells, called glia, which may lead to further loss of neurons. Eventually, the nerve cells in the brains of most Alzheimer""s patients develop tangles of a microtubule-associated protein, called tau, which are believed to be a response by the nerve cells to damage.
Progress in understanding the underlying mechanisms of Alzheimer""s disease has led to the development of various in vitro and in vivo models to identify compounds effective for preventing and/or treating Alzheimer""s disease and other neurodegenerative conditions. In one such in vitro model, compounds are evaluated for their ability to intervene in Axcex2(1-40) or Axcex2(1-42) beta-pleated sheet formnation. Since the deposition of amyloid xcex2-peptide is associated with the development of Alzheimer""s disease, compounds which effectively disrupt the formation of Axcex2(1-40) beta-pleated sheets are potentially useful for preventing and/or reversing Alzheimer""s disease-related amyloid deposits.
In another in vitro model, compounds are evaluated for their ability to protect against Axcex2(25-35)-induced neuronal cell loss in rat embryonic hippocampal neuronal/astrocyte cultures. As discussed above, patients with Alzheimer""s disease suffer a progressive loss of neuronal cells. Accordingly, compounds which are effective in this in vitro test are potentially useful for reducing or preventing neuronal cell loss in patients afflicted with Alzheimer""s disease or other neurodegenerative conditions.
A third in vitro Alzheimer""s disease model is based on the observation that xcex2-amyloid increases the release of cytokines, such as interleukin-1xcex2 (IL-1xcex2), interleukin-6 (IL-6) and tumor necrosis factor-xcex1 (TNFxcex1), in human monocyte cells induced with lipopolysaceharide (LPS). IL-1xcex2, IL-6 and TNFxcex1 are proteins associated with inflammatory and immune responses. As previously mentioned, the deposition of fibrils in the brains of Alzheimer""s patients is associated with inflammation of the surrounding support cells. See, S. D. Yan et al., Proc. Natl. Acad. Sci. USA. 94, 5296 (1997). Thus, compounds effective in this in vitro test are potentially useful for reducing and/or preventing the inflammation associated with Alzheimer""s disease.
Additionally, elevated levels of IL-1xcex2, IL-6. TNFxcex1 and other cytokines are associated with a wide variety of inflammatory and autoimmune conditions, including septic shock, rheumatoid arthritis, erythema nodosum leprosy, meningococcal meningitis, multiple sclerosis, systemic lupus and the like. See, L. Sekut et al., Drug News Perspect. 1196, 9, 261; and A. Waage et al., J. Exp. Med. 1989, 170, 1859-1867. Accordingly, compounds which inhibit the production of such cytokines are potentially useful for treating such inflammatory and autoimimune conditions.
Similarly, various in vivo disease models are available for identifying compounds useful for preventing and/or treating neurodegenerative, autoimmnune and inflammatory conditions. One such in vivo disease model is based on the observation that mammals suffer cognitive impairment when Axcex2(25-35) and ibotenate are injected into the hippocampus of their brain. Since amyloid xcex2-peptide deposits are associated with Alzheimer""s disease, compounds which effectively reduce the cognitive impairment caused by Axcex2(25-35)/ibotenate are potentially useful for the prevention and/or treatment of Alzheimer""s disease and other neurodegenerative conditions. Another in vivo disease model is based on the observation that certain strains of autoimmune mice develop cognitive deficits as they mature. See, for example, Forster et al., Behav. Neural Biology 1988, 49, 139-151. Thus, compounds which prevent or reduce such cognitive deficits are potentially useful for preventing and/or treating neurodegenerative and autoimmune conditions.
It has now been discovered that certain novel xcex1-aryl-N-alkylnitrone compounds effectively inhibit the formation of Axcex2(1-42) beta-pleated sheets and/or protect against neuronal cell loss and/or inhibit the release of cytokines, such as IL-1xcex2 and TNFxcex1. Additionally, in in vivo tests, these compounds have been found to reduce the cognitive impairment caused by Axcex2(25-35)/ibotenate and to reduce the cognitive deficits that develop in certain strains of autoimmune mice. Accordingly, such compounds are useful for the prevention and/or treatment of neurodegenerative, autoimmune and inflammatory conditions in mammals.
The xcex1-aryl-N-alkylnitrone compounds of this invention are also useful as analytical reagents for detecting free radicals. In this regard, the compounds of this invention function as xe2x80x9cspin trapsxe2x80x9d by reacting with unstable free radicals to form relatively stable free radical spin adducts which are observable by electron spin resonance (ESR) spectroscopy. Accordingly, when used as spin traps, the compounds of this invention allow free radicals to be identified and studied using ESR and related techniques.
This invention provides novel xcex1-aryl-N-alkylnitrone compounds which are useful as therapeutics for treating and/or preventing neurological, autoimmune and inflammatory conditions in mammals and as analytical reagents for detecting free radicals. In particular, the compounds of this invention are useful for preventing and/or treating Alzheimer""s disease.
Accordingly, in one of its composition aspects, this invention is directed to compounds of formula I: 
wherein
R1 is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;
R2 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R1 and R2 are attached to adjacent carbon atoms, R1 and R2 may be joined together to form an alkylenedioxy group;
R3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;
R4 is selected from the group consisting of hydrogen and alkyl;
R5 is selected from the group consisting of alkyl having at least 3 carbon atoms, substituted alkyl having at least 3 carbon atoms and cycloalkyl;
xe2x80x83provided that:
(i) when R2 and R3 are independently hydrogen or methoxy, R1 is not methoxy;
(ii) when R2, R3 and R4 are hydrogen and R5 is tert-butyl, then R1 is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;
(iii) when R2, R3 and R4 are hydrogen and R5 is isopropyl, then R1 is not 4-ethoxy;
(iv) when R1 and R2 are joined together to form a 3,4-methylenedioxy group and R3 and R4 are hydrogen, then R5 is not isopropyl or tert-butyl;
(v) when R2, R3 and R4 are hydrogen and R5 is 1-hydroxy-2-methylprop-2-yl, then R1 is not 2-ethoxy;
(vi) when R1 is 4-methoxy, R2 is 3-ethoxy, and R3 and R4 are hydrogen, then R5 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and
(vii) when R3 and R4 are hydrogen and R5 is tert-butyl, then R1 is not 4-methoxy when R2 is 2-fluoro, and R1 is not 2-methoxy when R2 is 4-fluoro.
Preferably, in the compounds of formula I above, R1 is selected from the group consisting of alkoxy, alkaryloxy and cycloalkoxy. More preferably, R1 is alkoxy having 1 to about 8 carbon atoms or alkaryloxy having 7 to about 10 carbon atoms. Particularly preferred R1 groups include methoxy, ethoxy, butoxy, pentyloxy, hexyloxy, cyclohexyloxy, heptyloxy, octyloxy, benzyloxy, 4-fluorobenzyloxy and 4-methoxybenzyloxy.
R2 is preferably selected from the group consisting of hydrogen, alkoxy and fluoro. More preferably, R2 is hydrogen, alkoxy having 2 to about 8 carbon atoms, or fluoro. Particularly preferred R2 groups include hydrogen, ethoxy and fluoro.
When R1 and R2 are attached to adjacent carbon atoms. R1 and R2 are also preferably joined together to form an alkylenedioxy group having 1 to about 6 carbon atoms. Particularly preferred alkylenedioxy groups include methylenedioxy and ethylenedioxy, provided that when R1 and R2 are joined together to form a 3,4-methylenedioxy group and R3 and R4 are hydrogen, then R5 is not isopropyl or tert-butyl.
Preferably, R3 is hydrogen or alkoxy. More preferably, R3 is hydrogen or alkoxy having 2 to 8 carbon atoms. Particularly preferred R3 groups include hydrogen and ethoxy.
R4 is preferably hydrogen or lower alkyl. More preferably, R4 is hydrogen or alkyl having 1 to 4 carbon atoms. Still more preferably, R4 is hydrogen.
R5 is preferably selected from the group consisting of alkyl having 3 to about 8 carbon atoms, substituted alkyl having 3 to 8 carbon atoms and cycloalkyl having 3 to about 10 carbon atoms. More preferably, R5 is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms.
Particularly preferred R5 groups include n-propyl, isopropyl, 1-methoxy2-methylproo-2-yl, n-butyl, but-2-yl, tert-butyl, 2-methylbut-2-yl, 3-methylbut-1-yl, 3,3-dimethylbut-2-yl, 4-methylpent-2-yl, 2,4-dimethyl-2-pentyl, 2,2,4,4-tetramethylpent-3-yl, cyclopropyl, cyclobutyl, tert-octyl (2,4,4-trimethylpent-2-yl), cyclopentyl, cyclohexyl, cyclooctyl, 1-adamantyl, 2-adamantyl, 3,5-dimethyl-1-adamantyl and benzyl. When R5 is adamantyl, 1-adamantyl is preferred.
Other suitable R5 groups include, by way of example, 1-phenylethyl, 1-phenylprop-2-yl, 2-phenylprop-2-yl, 2-benzylprop-2-yl, 2-(methoxycarbonyl)prop-2-yl, 1,3-dihydroxy-2-(hydroxymethyl)prop-2-yl, 1-sulfo-2-methylprop-2-yl, 4-fluorobenzyl, 3,4-dimethoxybenzyl, 3-thiomethoxybut-1-yl and 3-thiomethoxyprop-1-yl.
An especially preferred group of compounds of formula I are those in which R1 is a 2-ethoxy group; R2, R3 and R4 are each hydrogen; and R5 is as defined above.
Another especially preferred group of compounds of formula I are those in which R1 is a 4-ethoxy group; R2, R3 and R4 are each hydrogen; and R5 is as defined above.
Still another especially preferred group of compounds of formula I are those in which R1 is a 4-benzyloxy group; R2, R3 and R4 are each hydrogen; and R5 is as defined above.
Yet another especially preferred group of compounds of formula I are those in which R1 is a 3-ethoxy group; R2 is a 4-methoxy group; R3 and R4 are each hydrogen; and R5 is as defined above.
In a preferred embodiment, this invention is directed to a compound of formula II: 
wherein
R6 is selected from the group consisting of alkoxy having 1 to 8 carbon atoms, alkaryloxy having 7 to 10 carbon atoms, aryloxy having 6 to 10 carbon atoms and cycloalkoxy having 3 to 10 carbon atoms;
R7 is selected from the group consisting of alkoxy having 1 to 8 carbon atoms and fluoro, or when R6 and R7 are attached to adjacent carbon atoms, R6 and R7 may be joined together to form an alkylenedioxy group having 1 to about 6 carbon atoms;
R8 is selected from the group consisting of hydrogen and alkoxy having 1 to 8 carbon atoms; and
R9 is selected from the group consisting of alkyl having 3 to about 8 carbon atoms, substituted alkyl having 3 to about 8 carbon atoms and cycloalkyl having 3 to about 10 carbon atoms;
xe2x80x83provided that:
(i) when R7 is methoxy and R8 is hydrogen or methoxy, R6 is not methoxy;
(ii) when R6 and R7 are joined together to form a 3,4-methylenedioxy group and R8 is hydrogen, then R9 is not isopropyl or tert-butyl; and
(iii) when R6 is 4-methoxy, R7 is 3-ethoxy and R8 is hydrogen, then R9 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl.
In a preferred embodiment, R6 is alkoxy having 1 to 8 carbon atoms, R7 is alkoxy having 2 to 8 carbon atoms and R8 is hydrogen. In this embodiment, particularly preferred R6 groups include methoxy, ethoxy, butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy, and particularly preferred R7 groups include ethoxy. More preferably, R6 is methoxy and R7 is ethoxy.
In another preferred embodiment, R6 is ethoxy; and R7 and R8 are hydrogen.
In yet another preferred embodiment, R6 is benzyloxy, R7 is alkoxy having 1 to 8 carbon atoms, and R8 is hydrogen. In this embodiment, particularly preferred R7 groups include methoxy, ethoxy, butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy. In another preferred embodiment, R6 is benzyloxy; and R7 and R8 are hydrogen.
In still another preferred embodiment, R6 is alkoxy having 1 to 8 carbon atoms, R7 is fluoro and R8 is hydrogen. In this embodiment, particularly preferred R6 groups include methoxy, ethoxy, butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy.
In yet another preferred embodiment, R6 and R7 are joined together to form a methylenedioxy or ethylenedioxy group and R8 is hydrogen, provided that when R6 and R7 are joined together to form a 3,4-methylenedioxy group and R8 is hydrogen, then R9 is not isopropyl or tert-butyl.
In the above embodiments, R9 is preferably alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 10 carbon atoms. Particularly preferred R9 groups include n-propyl, isopropyl, 1-methoxy2-methylproo-2-yl, n-butyl, but-2-yl, tert-butyl, 2-methylbut-2-yl, 3-methylbut-1-yl, 3,3-dimethylbut-2-yl, 4-methylpent-2-yl, 2,4-dimethyl-2-pentyl, 2,2,4,4-tetramethylpent-3-yl, cyclopropyl, cyclobutyl, tert-octyl (2,4,4-trimethylpent-2-yl), cyclopentyl, cyclohexyl, cyclooctyl, 1-adamantyl, 2-adamantyl, 3,5-dimethyl-1-adamantyl, benzyl. When R9 is adamantyl, 1-admantyl is preferred. Especially preferred R9 groups are isopropyl, tert-butyl, 2,4-dimethyl-2-pentyl, tert-octyl, 1-adamantyl, cyclopropyl and cyclohexyl.
In another of its composition aspects, this invention is directed to each of the individual compounds:
xcex1-(4-heptyloxyphenyl)-N-tert-butylnitrone
xcex1-(4-hexyloxyphenyl)-N-n-propylnitrone
xcex1-(3-ethoxy4-methoxyphenyl)-N-tert-butylnitrone
xcex1-(4-ethoxyphenyl)-N-tert-butylnitrone
xcex1-(4-benzyloxy-3-methoxyphenyl)-N-tert-butyinitrone
xcex1-[3-(4-methoxyphenoxy)phenyl]-N-tert-butylnitrone
xcex1-(2-ethoxyphenyl)-N-tert-butylnitrone
xcex1-(3,4-ethylenedioxyphenyl)-N-tert-butylnitrone
xcex1-(4-ethoxyphenyl)-N-cyclohexylnitrone
xcex1-(4-benzyloxy-3-methoxyphenyl)-N-cyclohexylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-cyclohexylnitrone
xcex1-(3,4-ethylenedioxyphenyl)-N-yclohexylnitrone
xcex1-(4-ethoxy-3-methoxyphenyl)-N-cyclohexylnitrone
xcex1-(3,4-ethylenedioxyphenyl)-N-isopropylnitrone
xcex1-(3-ethoxy4-methoxyphenyl)-N-isopropylnitrone
xcex1-(2-ethoxyphenyl)-N-isopropylnitrone
xcex1-(2-ethoxyphenyl)-N-cyclohexylnitrone
xcex1-(4-benzyloxy-3-methoxyphenyl)-N-isopropylnitrone
xcex1-(4-ethoxy-3-methoxyphenyl)-N-isopropyinitrone
xcex1-(3-ethoxy-4-hexyloxyphenyl)-N-cyclohexylnitrone
xcex1-(4-benzyloxy-3-methoxyphenyl)-N-n-butylnitrone
xcex1-(4-ethoxy-3-methoxyphenyl)-N-n-butylnitrone
xcex1-(2-ethoxyphenyl)-N-n-butyinitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-n-butyinitrone
xcex1-(3-ethoxy-4-hexyloxyphenyl)-N-isopropylnitrone
xcex1-(3-ethoxy-4-hexyloxyphenyl)-N-tert-butylnitrone
xcex1-(2-fluoro-4-octyloxyphenyl)-N-tert-butylnitrone
xcex1-(2,4,6-triethoxyphenyl)-N-tert-butylnitrone
xcex1-(2,4,6-triethoxyphenyl)-N-cyclohexylnitrone
xcex1-(2-n-butoxyphenyl)-N-tert-butylnitrone
xcex1-(3,4-diethoxyphenyl)-N-tert-butylnitrone
xcex1-(2-fluoro-4-heptyloxyphenyl)-N-tert-butylnitrone
xcex1-(2-fluoro-4-ethoxyphenyl)-N-tert-butylnitrone
xcex1-(2-fluoro-4-ethoxyphenyl)-N-cyclohexylnitrone
xcex1-(2-ethoxyphenyl)-N-1-adamantylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-1-adamantylnitrone
xcex1-(4-ethoxyphenyl)-N-cyclopentylnitrone
xcex1-(4-ethoxyphenyl)-N-tert-octylnitrone
xcex1-(4-benzyloxyphenyl)-N-tert-butylnitrone
xcex1-(4-benzyloxyphenyl)-N-cyclopentylnitrone
xcex1-(4-benzyloxyphenyl)-N-cyclohexylnitrone
xcex1-(2-ethoxyphenyl)-N-cyclopentylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-tert-octylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-(2,4-dimethyl-2-pentyl)nitrone
xcex1-(4-ethoxyphenyl)-N-n-butylnitrone
xcex1-(2-ethoxyphenyl)-N-benzylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-(2,2,4,4-tetramethylpent-3-yl)nitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-(4-methylpent-2-yl)nitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-but-2-ylnitrone
xcex1-(2-ethoxyphenyl)-N-but-2-ylnitrone
xcex1-[4-(4-fluorobenzyloxy)phenyl]-N-tert-butylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-cyclopentylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-n-propylnitrone
xcex1-(4-benzyloxyphenyl)-N-n-propylnitrone
xcex1-(4-benzyloxyphenyl)-N-isopropylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-(2-methylbut-2-yl)nitrone
xcex1-(2-ethoxyphenyl)-N-(2-methylbut-2-yl)nitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-cyclooctylnitrone
xcex1-(2-ethoxyphenyl)-N-cyclobutylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-cyclobutylnitrone
xcex1-(4-benzyloxyphenyl )-N-cyclobutylnitrone
xcex1-(4-benzyloxyphenyl)-N-tert-octylnitrone
xcex1-[4-(4-fluorobenzyloxy)phenyl]-N-cyclohexylnitrone
xcex1-(2-ethoxyphenyl)-N-tert-octylnitrone
xcex1-[4-(4-fluorobenzyloxy)phenyl]-N-isopropylnitrone
xcex1-(2-ethoxyphenyl)-N-cyclooctylnitrone
xcex1-(4-benzyloxyphenyl)-N-cyclopropylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-cyclopropylnitrone
xcex1-(4-benzyloxyphenyl)-N-cyclooctylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-(3,5-dimethyl-1-adamantyl)nitrone
xcex1-(4-benzyloxyphenyl)-N-1-adamantylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-(1-methoxy-2-methylprop-2-yl)nitrone
xcex1-(4-benzyloxyphenyl)-N-2-adamantylnitrone
xcex1-(4-ethoxyphenyl)-N-cyclooctylnitrone
xcex1-(4-ethoxyphenyl)-N-1-adamantylnitrone
xcex1-[4-(4-methoxybenzyloxy)phenyl]-N-tert-butylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-(3-methylbut-1-yl)nitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-cyclooctylnitrone, and
xcex1-[4-(4-fluorobenzyloxy)phenyl]-N-cyclopentylnitrone.
Particularly preferred compounds include:
xcex1-(2-ethoxyphenyl)-N-tert-butylnitrone
xcex1-(2-ethoxyphenyl)-N-cyclohexylnitrone
xcex1-(4-ethoxyphenyl)-N-cyclohexylnitrone
xcex1-(4-benzyloxyphenyl)-N-tert-butylnitrone
xcex1-(4-benzyloxyphenyl)-N-cyclopentylnitrone
xcex1-(3-ethoxy-4-methoxyphenyl)-N-adamantylnitrone, and
xcex1-(3-ethoxy-4-methoxyphenyl)-N-tert-octylnitrone.
In another of its composition aspects, this invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I: 
wherein R1-R5 are as defined above.
In additional composition aspects, this invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula II above.
As previously mentioned, the xcex1-aryl-N-alkylnitrone compounds of this invention have been discovered to inhibit the formation of Axcex2(1-42) beta-pleated sheets and/or to protect against Axcex2(25-35)-induced neuronal cell loss and/or to reduce xcex2-amyloid-induced release of cytokines, such as IL-1xcex2 and TNFxcex1, in human monocyte cells. Such compounds have also been found to reduce the cognitive defects caused by Axcex2(25-35)/ibotenate as well as those which develop in certain strains of autoimmune mice. Compounds having such properties are useful for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions.
Accordingly, in one of its method aspects, this invention is directed to a method for treating a patient with a neurodegenerative disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective neurodegenerative disease-treating amount of a compound of formula I or formula II above.
In another of its method aspects, this invention is directed to a method for preventing the onset of a neurodegenerative disease in a patient at risk for developing the neurodegenerative disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective neurodegenerative disease-preventing amount of a compound of formula I or formula II above.
In preferred embodiments of this invention, the neurodegenerative disease treated and/or prevented in the above methods is Alzheimer""s disease, Parkinson""s disease, HIV dementia and the like.
In still another of its method aspects, this invention is directed to a method for treating a patient with an autoimmune disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective autoimmune disease-treating amount of a compound of formula I or formula II above.
In yet another of its method aspects, this invention is directed to a method for preventing the onset of an autoimmune disease in a patient at risk for developing the autoimmune disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective autoimnmune disease-preventing amount of a compound of formula I or formula II above.
In preferred embodiments of this invention, the autoimmune disease treated and/or prevented in the above methods is systemic lupus, multiple sclerosis and the like.
In still another of its method aspects, this invention is directed to a method for treating a patient with an inflammatory disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory disease-treating amount of a compound of formula I or formula II above.
In yet another of its method aspects, this invention is directed to a method for preventing the onset of an inflammatory disease in a patient at risk for developing the inflammatory disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory disease-preventing amount of a compound of formula I or formula II above.
In preferred embodiments of this invention, the inflammatory disease treated and/or prevented in the above methods is rheumatoid arthritis, septic shock, erythema nodosum leprosy, septicemia, adult respiratory distress syndrome (ARDS), inflammatory bowel disease (IBD), uveitis and the like.
In another of its aspects, this invention is directed to the use of a compound of formula I or formula II above in the manufacture of a formulation or medicament for a medicinal treatment. Preferably, the medical treatment is the therapeutic or prophylactic treatment of a neurodegenerative disease, an autoimmune disease or an inflammatory disease.
Particularly preferred compounds include those represented in Tables I and II below.